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. 2016 Feb 17:6:21592.
doi: 10.1038/srep21592.

"VSports在线直播" Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis

Xi Cao  1   2 , Fangyuan Yang  1   2 , Tingting Shi  1   2 , Mingxia Yuan  1   2 , Zhong Xin  1   2 , Rongrong Xie  1   2 , Sen Li  1   2 , Hongbing Li  1   2 , Jin-Kui Yang  1   2
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Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis

Xi Cao et al. Sci Rep. .

"VSports最新版本" Abstract

The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2(-/y)) mice VSports手机版. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2(-/y) mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1-7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what's more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1-7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1-7)/Mas axis in prevention and treatment of hepatic lipid metabolism. .

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Figures

Figure 1
Figure 1. The absence of ACE2 aggravated the development of hepatic steatosis in ACE2−/y mice.
(A) Representative images of liver sections from WT and ACE2−/y mice stained with Oil-Red-O (n = 5/each group). (B–D) The liver weight, hepatic triglyceride and cholesterol levels were determined (n = 8/each group). *P < 0.05 and ***P < 0.001 versus WT by Student’s t test.
Figure 2
Figure 2. ACE2 regulated hepatic gene expressions involved in lipid-metabolizing, oxidative stress and inflammation in the liver of ACE2−/y mice.
(A) Relative protein levels of lipid-metabolizing (ACCα, SREBP-1c, LXRα, FAS, AdipoR1 and UCP-2). (B) Relative gene expression levels of fatty acid oxidation-related genes (PGC-1α, CPT-1α, PPARα, PPARγ and MCAD). (C) Relative protein levels of oxidative stress signaling (catalase, GPX1 and SOD2), and (D) inflammation (TNF-α, MCP-1 and IL-8). The data are presented as the mean ± SD of n = 4 independent experiments in ACE2−/y mice. *P < 0.05 and **P < 0.01 versus WT mice by Student’s t test.
Figure 3
Figure 3. Hepatic overexpression of ACE2 ameliorated hepatic steatosis of db/db mice.
(A) Representative images of liver sections from db/db, db/db + GFP and db/db + ACE2 mice stained with Oil-Red-O. Quantitative assay of (B) AngII, (C) triglyceride and cholesterol, (D) ALT and AST levels in ACE2-overexpressing db/db mice. *P < 0.05versus db/db + GFP mice (n = 6). (E) Relative gene expression levels of fatty acid oxidation-related genes (PGC-1α, CPT-1α, PPARα, PPARγ and MCAD). *P < 0.05 versus db/db + GFP by Student’s t test.
Figure 4
Figure 4. Ang-(1–7)/ACE2 ameliorated hepatic steatosis in FFA-induced HepG2 cells.
Cells were exposed to 2 mM of FFA (2:1, oleate: palmitate) for 24 h. FFA-induced hepatic steatosis in HepG2 cell treated with Ang-(1–7) or A779. (A) Analyze lipid accumulation by Oil Red O staining. (B) Intracellular lipids were stained with Nile red, and the fluorescence intensity of Nile red was measured by flow cytometry. (C) Intracellular lipids content analysis following ACE2 overexpression. (D) Relative protein levels of ACCα, SREBP-1c, LXRα, FAS, UCP-2 and AdipoR1 in ACE2-overexpressing HepG2 cells and FFA-induced HepG2 cells. (E) Relative protein levels of ACCα, SREBP-1c, LXRα and FAS in API-2 or MK-2206-treated ACE2-overexpressing HepG2 cells. Cells were treated with API-2 (20 μM) and MK-2206 (10 μM) for 24 h. The data are presented as the mean ± SD of n = 3 independent experiments in HepG2 cells. *P < 0.05 and **P < 0.01 versus GFP group by one-way ANOVA; #P < 0.05 versus ACE2 group by one-way ANOVA.
Figure 5
Figure 5. Ang-(1–7)/ACE2 inhibit oxidative stress and inflammation in FFA-induced HepG2 cells.
(A) The levels of intracellular ROS were stained with DCF-DA and the fluorescence intensity of DCF-DA was measured by flow cytometry. (B) Relative protein levels of anti-oxidative stress related proteins (catalase, GPX1 and SOD2) and inflammation related proteins (TNF-α, MCP-1 and IL-8) in ACE2-overexpressing HepG2 cells. The data are presented as the mean ± SD of n = 3 independent experiments in HepG2 cells. *P < 0.05 and **P < 0.01 versus control or empty vector by one-way ANOVA.
Figure 6
Figure 6. ACE2 activated Akt through the ATP/P2 receptor/CaM signal pathway.
(A) The intracellular and extracellular ATP levels in ACE2-overexpressing HepG2 cells. (B) ACE2-induced Akt activation was inhibited by the IP3R antagonist (2-APB), the ATP receptor P2 antagonist (PPADS), and the CaM antagonist (CPZ). Infected HepG2 cells were treated with 2-APB (10 μM), PPADS (50 μM) or CPZ (100 μM) for 1 hour before pAkt levels was measured. The data are presented as the mean ± SD of n = 3 independent experiments in HepG2 cells. *P < 0.05 versus control cells, #P < 0.05 versus Ad-ACE2 infected cells without 2-APB, PPAD or CPZ treatment (n = 3). (C) ACE2-induced Akt activation was partially dependent on the presence of extracellular calcium. Infected cells were treated with calcium free medium HANK’S for 2 hours before pAkt levels were assayed. The data are presented as the mean ± SD of n = 3 independent experiments in HepG2 cells. *P < 0.05 versus control cells; #P < 0.05 versus Ad-ACE2 infected cells with calcium (n = 3).
Figure 7
Figure 7. Mechanisms involved in ACE2/Ang-(1–7)/Mas axis activation-induced improvement of hepatic lipid metabolism.
The up- or down-regulation of metabolic pathways is indicated by arrows (↑ for up-regulation and ↓ for down-regulation).
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